INTRODUCTION
Traditionally solid oral dosage firms have been designed to release their drug load in upper regions of G.I.T. Where conditions are generally more suited to drug dissolution and absorption. Recently greater emphasis has been placed on controlling the rate and site of drug release from oral formulations for the purpose of patient compliance and treatment efficiency.
The colonic region of G.I.T is one that would benefit from the development and such modified release technologies. Although considered by many to be an innocence organ that may simple functions in the form of water and electro light absorption and the formation storage and explosion of fecal material, the colon is valuable to a No of disorders including alternative qualities corn's disease irritable bower syndrome and carcinomas. Targeted drug delivery to the colon would there fore ensure direct treatment at the disease site lower closing and favour systemic side effects.
In addition to local therapy, the color can also be utilized as a portal for entry of drug into the systemic circulation. eg:- molecules that are degraded parry absorbed in upper get, such as peptides and proteins, may be better absorbed from more being environment of colon . In addition systemic absorption from colon can also be used as a means of achieving chemotherapy for diseases that are sensitive to circadian rhythms such as asthma angina, orthotics.
Successful colonic drug delivery careful consideration of a large number of factors, including the properties of drug, the type of delivery system and in interaction with the healthy or diseased gut for instance, regardless of whether a local or systemic effect is required, the administrate drug must first dissolve in lonely fluid of colon. Overseas, there is less free fluid in colon than is small intestine and hence, dissolution could be drug may need to be delivered in a pre-established form, or delivery should be directed to proximal colon, as a fluid gradient exists in colon with more free water present in proximal colon than is distal colon.
Aside from drug solubility, the stability of drug in colonic environment is a further factor that warrants attention. The drug could bind in a non specific manner to directory residues, intestinal secretions, or general faucal matter, thereby reducing the connection of free drug. Moreover, the resident microflora caved also effect colonic performance via degradation of drug.
In terms of systematic therapy via the colon, the small internal surface area and relative 'tightness' of tight junction is colon could restrict drug transport across mucosa a enzymes that are capable of metabolizing endogenous and exogenous subtracts such as carbohydrates , proteins, that escape digestion in upper G.I tract ,.Therefore materials that are recalcitrant to the conditions of stomach and small intensive, yet suspicious to degradation by bacterial enzymes within colon, can be utilized as carriers for drug delivery to colon.
Eg:- This principle has been exploited commercially to deliver 5 anniosalicylic acid to the colon by way of a prodrug career. The prodrug sulphasalazine consists of two separate moieties, sulphaphyridine and 5-aminosalcylic acid, linked by as azo-bond. The prodrug posses through the upper gut intract, but once in colon the azo-bond is cleave by the host bacteria, liberating the carrier molecule sulphaphyridine and pharmacologically active agent 5- aminosalicyclic acid and its systematic circulation. To a certain earnest, the longer residence time in colon (up to 5 says) may compensate for these limitations. There is also evidence to suggest that the activity of the cyclo chrome p 450 3A class of drug metabolizing enzymes is lower is mucosa of colon than small intensive. Therefore colonic delivery may lead to elevated plasma levels and improved oral bioavailability for drugs that are substrates for this enzyme class.In relation to delivery modified release formulations are usually based on either a single unit tablets and bicapsular) or multi unit (Pellets & granules) plat form design.
TARGETTING MECHANISM OF DRUG ACTING ON COLON
1. Pre-dependent delivery
2. Time-dependent delivery
3. Pressure-dependent delivery
4. Bacteria dependent delivery
Successful colonic drug delivery requires careful considerations of a number of factors, including the properties of drug, the type of delivery system and its interaction with the healthy or diseased gut.
1. PH-DEPENDENT DELIVERY
Pre-sensitive enteric coatings have been used routing to deliver drugs to small intensive. These polymer coatings are insensitive to the acidic conditions of stomach yet dissolve at the higher PH environment of small intestine. This Ph differential principle has also been attempted for colonic delivery purposes although polymers used for solenoid targeting and to have a threshold PH for dissolution that is HIGHER than those used in conventional enteric coating applications. Most commonly co-polymers of methacrylic acid and methyl metha crylate that dissolve at PH 5 PH 7 have been investigated./ This approach is based on assumption that G.I PH increases progressively from the small intestine to colon. In fact, the in distal small intestine is usually around 7.5, while the H in proximal colon is closer to 6 These delivery systems therefore have a tendency to release their drug load prior to reaching colon.
To overcome the problem of premature drug release a copolymer of methacrylic, acid, methyl methacrylate and ethy threshold OH, has been developed recently.
The inter subject variability in G>I PMand possibly certain other intersect various such as electrolite concentration.and transit time will therefore impact on in vivo behaviour of PH responsive systems, ranging from early drug release is small intensive to are release at all with the formulation passing throughout gut intact. The latter situation will also arise when PH of colon, and possibility the small intensive is considerably lower than normal as the case in patients with creative qualities.. In spite of their limitations, PH sensitive delivery systems are commercially available for mesalazine in and budesonide for treatment of ulcerative colitis & crohn's disease, respectively.
2. TIME DEPENDENT DELIVERY
It has also been proposed as a means of targeting the colon. Time dependence systems release their drug load after a pre programmed time delay. To attain colonic release, the log, time should equateto time taken for system to react the colon. This time is difficult to predict in advance,although a log time of five hours is usually considerated sufficient, given that small intential transit time is reported to be relatively consitant at three to four hours. One of the earliest system to utilise this principle was the pulsincap device. System consisit of an importable capsule fined with drug and stoppered at one end with a hydroges plug, on contact with gastrointential fluids, the plug hydratres and swells and after a set log time, ejects from the capsule body, thereby allowing drug release to occur. The log time is controlled by the size and composition of play. The influ
BACTERIA DEPENDENT DELIVERY
The resident g.i.bacteria provide a further means of effecting drug release in colon, Thesse bacteria predoninatly colonise the distas region of g.i tract where baterial count in the colon is 10' per gramme as compared with 10'per gramme in uper small inestine moreover, 400 different species are present colonic bacteria are pre dominantly in nature and produce ence of gastric copying on performance of pulsincap was reduced by a application of an outer enteric coat. The outer enteric coat dissolves on entering the small intenstine to reveal by either swelling, eroding or dissolving over a period of time equivalant to small intential transit.
Although the use of an over enteric coat overcomes to a certain attent the availability in G.I emptying, the intrisic problems with such systems is over all inter and intra subject variability in transit. Transit is slower in evening as compared with morning.
3. PRESSURE DEPENDENT DELIVERY
G.I pressure has also been utilised drug release in destal gut.This pressure which is generated via muscular contraction of gut wall for gtinding and proposition of intestial contents, varioes in intesity and duration throught the g.itract, with the colon considered to have a higher internal pressure due to process that ocur during stool formation. The system have therefore been developed to resisst the pressure of upper g.i tract but in rupture response to the raised pressure of colon.capsule shells fabricated from water insolube polymer entry cellulose have been used for this purpose. The system can be modified to withstand and rupture at different pressors by changing the size of capsule and thicknessof capsule shell wall.
enzynes that are capable of metabolishing endogenous and exogeneous substracts such as carbohydrates ,protines,that escape digestion in upper g.i tract ,.Therefore materials that are recalcitrant to the conditions of stonach and small intensive, yet suspecious to degradation by bacterial enzynes within colon, can be ulilised as carriers for drug delivery to colon.
Eg:- This principle has been expoited commercially to deliver 5 anniosalicylic acid to the colon by way of a prodrug career. The prodrug sulphasalazinc consists of two separate moities, sui phaphyridine and 5-aminosalcylic acid, linked by as azo-bond. The prodrug posses through the upper gut intract,but once in colon the azo-bond is cleaveal by the host bacteria, liberting the carrier molecule sulphaphyridin and pharmacologicary active agent 5- aminosalicyclic acid.
PHARMACEUTICAL APPROACH TO COLON TARGETED DRUG DELIVERY
COATING WITH BIODURABABLE POLYMERS
The bio environment inside the human G.I.T is characterized by presence of complex microflora especially the colon that is rich in micro organizing that are involved in the process of reduction of dietary component or other materials. Drugs that are coated with polymers, which are showing degradability due to influence of colonic micro organisms, can be exploited in designing drugs for colon targeting. These bacterial degradable polymers especially also polymers have been explored in order to release as orally administrated drug in colon. Actually upon passage of dosage from through G.I.T it remains intact in stomach and small intestine where very little microbially degrades activity is present that is quiet insufficient for cleavage of polymer coating, Release of the drugs from azo polymer coated formulation is supposed to take place after reductionism thus degradation of azo bonds by azo reductase enzymes released by azo batters in colonic microflora.
Mesalazine is the active component of sulfasalazine exerting a predominant local topical action independent of blood levels. Its effectiveness depends on the site of ulceration in relation to the drug's dissolution profile. This is very important when choosing aminosalicylate preparations, as illustrated in Figure 11.4.
The optimal dose of sulfasalazine to achieve and maintain remission is usually in the range of 2-4g pe day in four divided doses. Acute attacks require 4-8g per day in divided doses until remission occurs, but at these doses associated side-effects begin to appear.
Of patients taking sulfasalazine, 30% experience adverse effects that are either dose-related, dependent on acetylator phenotype or idiosyncreatic non-dose, related reactions. The first group includes nausea, vomiting, headache, malaise, haemolytic anaemia, reticulocytosis, and methamemoglobulinaemia. The second includes skin rash, hepatic and pulmonary dysfunction, aplastic anaemia and reversible azoospermia. Adverse effects usually occur during the first 2 weeks of therapy, the majority being related to serum sulfapyridine levels.
Many of the adverse effects listed above can be avoided by using one of the aminosalicylate formulations now available.
Formulation. As mesalazine is unstable in acid medium and rapidly absorbed from the gastrointestinal tract, the new preparations have been developed using three different approaches.
- A mesalazine tablet coated with a pH-dependent acrylic resin
Ethylcellulose-coated mesalazine granules diazotization of mesalazine to itself or to an inert carrier.
Asacol contains 400 mg of mesalazine coated with an acrylic resin, Eudragit-S, that dissolves at pH 7 and releases mesalazine in the terminal ileum and the colon. Salofakd tablets are similar fo;umulation containing 250 mg mesalizine with sodium carbonate-glycine and a cellulose ether, coated with Eudragit-L which dissolves at pH 6 and above, releasing mesalaxine in the jejunum and ileum.
Table 11.4 comprasion of available oral aminosalicylate premations for patients with inflammatory bowel disease
| Generic (proprietary) name | Formulation | Release profile | Site of release |
| Sulfasalazine (Salazpyrin) | Compressed tablet. Plain and film coated | Azo-linked, independent at pH | Terminal ileum and colon |
| Mesalazine (Asacol) | Compressed tablet, acrylic coating | Acrylic coating dissolving at pH 7 | Terminal ileum and colon |
| Mesalazine (Salofalk and generic forms) | Compressed tablet and/or capsule acrylic coating | Acrylic coating dissolving at pH 6 | Mid-jejunum ileum and colon |
| Mesalazine (Pentasa) | Microgranules coated with ethycellulose and compressed into tablets. Granules also available | Disintegration not dependent on pH. Slow dissolution rate | Stomach, duodenum, jejunum, ileum and colon |
| Olsalazine (Dipentum) | Hard gelatin capsules and tablets, uncoated | Azo-linked disintegration independent of pH | Terminal ileum and colon |
| Balsalazide (Colazide) | Hard gelatin caplules | Azo-linked disintegration independent of pH | Terminal ileum and colon |
| Polyasa | Compressed tablet | Azo linked disintegration in dependent of ph | Terminal ileum and colon |
COVALENT LINKAGE OF THE DRUG WITH A CARRIER
It involves the formation of a covalent linkage between drug and carrier in such a manner that upon oral administration the moiety remains intact in the stomach and small intestine.
This approach chiefly involves the formation of prodrug, which is a pharmacologically inactive derivative of a parent drug molecule that requires spontaneous or enzymatic transformation in the biological environment to release the active drug. Formation of prodrugs has improved delivery properties over the parent drug molecule. The problem of stability of certain drugs from the adverse environment of the upper GIT can be eliminated by prodrug formation, which is converted into parent drug molecule once it reaches into the colon. Site specific drug delivery through site specific prodrug activation may be accomplished by the utilization of some specific property at the target site, such as altered pH or high activity of certain enzymes relative to the non-target tissues for the prodrug-drug conversion.
AZO BOND CONJUGATES
The intestinal microflora is characterized by a complex and relatively stable community of microorganism, many with physiological functions, which play vital roles in health and disease. In addition to protection of the patient against colonization of the intestinal tract by potentially pathogenic bacteria, the indigenous microflora are responsible for a wide variety of metabolic processes, including the reduction of nitro and azo groups in environmental and therapeutic compounds.
Sulphasalazine was introduced for the treatment of rheumatoid arthritis and anti-inflammatory disease. Chemically it is salicylazosulphapyridine (SASP), where sulfapyridine is linked to a salicylate radical by an azo bond. When taken orally, only a small proportion of the ingested dose is absorbed from the small intestine and the bulk of the sulphasalazine reaches the colon intact. There it is split at the azo bond by the colonic bacteria with the liberation of sulphapyridine (SP) and 5 ASA. However sulphapyridine is seems to be responsible for most of the side effects of sulphasalazine and hence various new approaches for the treatment of IBD have emerged.
GLYCOSIDE CONJUGATES
Steroid glycosides and the unique glycosidase activity of the colonic microflora frorm the basis of a new colon targeted drug delivery system. Drug glycosides are hydrophilic and thus, poorly absorbed from the small intestine. Once such a glycoside reaches the colon it can be cleaved by bacterial glycosidases, releasing the free drug to be absorbed by the colonic mucosa.
The major glycosidases identified in human feces are b-D-galactosidase, b-D glucosidase, a--L-arabinofuranosidase, b-D-xylopyranosidase. These enzymes are located at the brush border and hence access to the substrate is relatively easy. In the plant kingdom numerous compounds are found as glycosides. Certain drugs act as glycon and can be conjugated to different sugar moieties which results in the formation of glycosides. Due to the bulky and hydrophilic nature of these glycosides, they do not penetrate the biologicl membrane upon ingestion. Various naturally occurring glycosides, e.g the sennosides, have been used for laxative action for ages. When taken orally, intact sennosides are more efficient as laxative than sugar free aglycones. These sennosides are activated are activated by colonic microflora to generate rhein anthones, which gives the desired laxative effect. Glycosidase activity of the GIT is derived from anaerobic microflora in the large bowel or the sloughed or exfoliated cells of the small intestine.
GLUCURONIDE CONJUGATES
Glucuronide and sulphate conjugation is the major mechanisms for the inactivation and preparation for clearance of a variety of drugs. Bacteria of the lower GIT, however, secrete b-glucuronidase and can deglucuronidate a variety of drugs in the intestine. Since the deglucuronidation process results in the release of active drug and enables its reabsorption, glucuronide prodrugs would be expected to be superior for colon targeted drug delivery.
Morphine-dependent rats were used to evaluate the effects of the narcotic antagonists, naloxone and nalmefene, and their glucuronide conjugates on the gastrointestinal tract and various parameters of brain-mediated withdrawal. When administered subcutaneously nalmefene hydrochloride caused a dose-dependent tail skin temperature increase, whereas nalmefene glucuronide was ineffective Malmefene precipitated brain-mediated morphine with drawal at doses as low as 10mg/kg, whereas nalmefene glucuronide was ineffective at doses as high as 1mg/kg. After per oral administration of the drugs, nalozone hydrochloride and nalmefene hydrochloride caused diarrhea, withdrawal behavior and tail skin temperature responses by 15 minutes. In contrast, after per oral administration of the glucuronide conjugate of either narcotic antagonist, diarrhea was delayed for 75 to 203 minutes. This latency probably reflects the required transit time to the lower gastrointestinal tract. About 0.2 to 0.5% of the dose of the narcotic antagonist administered orally as the glucuronide was absorbed systemically. These results indicate that per oral administration of the glucuronide conjugates of nalox one and nalmefene results in delivery of the narcotic antagonists to the colon. Haeberlin et al. prepared a dexamethasone b-D-glucuronide prodrug.
CYCLODEXTRIN CONJUGATES
Cyclodextrins (CyDs) are clyclic oligosaccharides consisted of six to eight glucose units through a-1,4 glucosidic bonds and have been utilized to improve certain properties of drugs such as solubility, stability and bioavalability. The interior of these molecules is relatively lipophilic and the exterior relatively hydrophilic, they tend to form inclusion complexes with various drug molecules. They are known to be barely capable of being hydrolyzed and only slightly absorbed in passage through the stomach and small intestine, however, they are fermented by colonic microflora into small saccharides and thus absorbed in the large intestine. Because of their bioadaptability and multi functional characteristics, CyDs are capable of alleviating the undesirable properties of drug molecules in various routes of administration through the formation of inclusion complexes. In an oral drug delivery system, the hydrophilic and ionizable CyDs can serve as potent drug carriers in the immediate release and delayed release formulations, respectively, while hydrophobic CyDs can retard the release rate of water-soluble drugs. Since CyDs are able to extend the function of pharmaceutical additives, the combination of molecular encapsulation with other carrier materials will become effective and a valuable tool in the improvement of drug formulation. Moreover, the most desirable attribute for the drug carrier is its ability to deliver a drug to a targeted site, conjugates of a drug with CyDs can be a versatile means of constructing a new class of colon targeting prodrugs.
It has been proved through a study in healthy human volunteers that b CyDs are meagerly digested in small intestine but are completely degraded by the microflora of the colon. Most bacterial strains that are isolated from human being are capable of degrading CyDs. It has been proved by their ability to grow on cyclodextrins by utilizing them as the sole carbon source and by the stimulation of cyclodextrinase activity by as low as 2-4h of exposure to cyclodextrins. This property of the drug may be exploited for the formation of colon targeted drug delivery systems. Several CyD conjugates have been prepared and the enantioselective hydrolysis has described.
DEXTRAN CONJUGATES
Dextran ester prodrug was prepared and in vitro release revealed that release of naproxen from prodrug was several folds higher in caecum homogenates than in control medium or homogenates of the small intestine of pig. The bioavailability of naproxen after oral administration of a dextran T-70 naproxan ester prodrug in pigs was assessed by Harboe et al. compared to the administration of an oral solution of an equivalent dose of naproxen the average absorption fraction for the conjugate amounted to 91%. It was established that several features of the prodrug indicated that naproxan was released from the prodrug prior systemic absorption and that drug activation involved the action of one or more enzyme systems located in the gastrointestinal tract. It was observed in rabbits, the plasma concentration-time curves for the conjugate were characterized by an initial lag time of about 2-3h, whereas naproxan was detected in plasma immediately after per oral administration of the drug compound per sec. The distribution of the prodrug along the GIT at various times after conjugate administration was assessed qualitatively by HPLC analysis of conjugated and free naproxan in various segments of the GIT. From these experiments it was suggested that drug regeneration was effective in the bowel below the ileum.
AMINO-ACID CONJUGATES
Due to the hydrophilic nature of polar groups like NH2 and COOH, that is present in the proteins and their basic units, they reduce the membrane permeability of amino acids and proteins. Various prodrugs have been prepared by the conjuagation of drug molecules to these polar amino acids. Non-essential amino acids such as tyrosine, glycine, methionine and glutamic acid were conjugated to SA. The salicyluric acid was found to be metabolized to SA by the microorganisms of the intestinal flora of rabbit and dog. The prodrug was absorbed into the systemic circulation from the upper GIT and hence it was proved unsuitable for delivery of drugs to the colon. By increasing the hydrophilicity and chain length of the carrier amino acid and decreasing the membrane permeability of conjugates. This conjugate showed splendid results with minimal absorption and degradation in the upper GIT and proved suitable for colon targeted delivery of SA.
POLYMERIC PRODRUGS
Azo-linked polymeric prodrugs of 5-ASA were prepared and evaluated in simulated human intestinal microbial ecosystem. Polyamides containing azo grups in the backbone were prepared and tested in vitro in a reductive buffer or in the bioreactor medium. It was demonstrated that for the hydrophobic polymer, reduction stops at the hydrazine stage whereas for a hydrophilic analogue reduction with formation of amine occurred. The amount of the drug released depend on the nature of the polymer and can approach that of low molecular weight prodrugs.
USES
I.
LOCAL ACTIONS
1. Ulcerative colities.
2. CHRON'S disease.
3. Irritable bower syndrome
4. Metastatic human colon cancer
II. SYSTEMIC ACTIONS
Molecules degraded/poorly absorbed from upper G.I.T such as peptides and proteins are better absorbed from colon,
For achieving chemotherapy for diseases that are sensitive to circadian rhythm such as Asthma, angina, arthritis
ADVANTAGE AND DISADVANTAGE
ADVANTAGE
- Patient compliance and treatment efficacy
- Useful in treatment of ulcerative colitis, chron's disease, irritable bowel syndrome and carcinomas
- Low dose is required ,so less side effect
- Used for local and systemic action
Gastric irritation can be avoided
DISADVANTAGE
- there is less fluid in colon than in small intestine and hence dissolution is a problem for water soluble drugs
- binding of drug to dietry residues ,intestinal secretions etc reduce concentration of free drugs
- some micro flora may degrade the drug
small luminal surface area and relative tightness of tight Jouncions in colon, delay the systemic absorption.
Onset of action is slow.CONCLUSION
The colonic region of gastro intestinal tract become and increasingly important site for drug delivery and absorption. The targeted drug delivery would offer considerable therapeutic benefits to patients, in terms of both local and systemic treatment. Systems that rely on gastrointestinal P4 transit tine or pressure for release are unlikely to function as reachable and effective colon specific delivery vehicles colon specialty is more likely to be achieved to systems that utilize natural materials that are degraded by bacterial enzymes of colonic origin. Moreover the cost and case of manufacture delivery system are further considerations that will impact on its likely commercialization and hence, availability to patient .A bacteria sensitive natural film coating that can be applied to a range of solid oral dosage forms using conversional processing technology would therefore appear to be delivery system of choice.
In summary two controlled release mechanism, i.e, time and p4-dependent, could achieve colonic-specific drug delivery following oral administration. In addition, both CDDS were relatively in expensive and easy to be manufactured using conventional pharmaceutical coating technique, and provided the promising candidates for specifically delivering drug to targeted colon region, in particular for DS and 5-ASA in this study, respectively
